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Genetic counseling: Galactosemia
Galactosemia Introduction *Disorder of galactose metabolism *Usually caused by deficient activity of enzyme galactose-phosphate uridyltransferase (GALT) *Autosomal recessive inheritance Diagnosis *Detected in virtually 100% of affected infants if included in newborn screen *Presents with poor suck, failure to thrive, bleeding diathesis, and jaundice, hypoglycemia, hepatocellular damage, and hyperammonemia *If untreated in infants can result in **Liver damage **Sepsis **Mental retardation *If suspected remove lactose from diet while tests are pending *If placed on lactose - galactose restricted diet than symptoms quickly resolve and can prevent permanent damage *Despite early treatment still at increased risk for **developmental delays **speech problems **abnormalities of motor function **poor growth **poor intellectual function **premature ovarian failure in women *With continued dietary management-- many individuals with galactosemia have good health, and are able to lead independent lives *Outcome can be based on GALT activity, genotype, age at diagnosis and compliance with lactose restriction *Diagnosis made by measuring erythrocyte GALT activity and isoelectric focusing of GALT **Done for infants who have a positive newborn screening test, symptoms, or a positive clinitest reaction (copper oxidizing aldehyde) and a negative glucostix reaction (glucose oxidase impregnated strip) **Classic galactosemia G/G homozygote activity less than 5% of control **Heterozygote G/N GALT activity about 50% of control **Duarte variant activity between 5-20% (express stronger activity bands, which move toward the anode and lower pH) *Mol gen testing of GALT gene (chromosome 9p13) clinically available for biochemically confirmed galactosemia and is used for: **prognostic information **heterozygote detection **genetic counseling, **prenatal diagnosis *Biochemical assays also necessary for diagnosis and as therapeutic parameters include: **Erythrocyte galactose-1-phosphate -- metabolism of this precursor is blocked in the GALT reaction sequence --Concentration of erythrocyte galactose-1-phosphate exceeds 2mg/dl in untreated individuals and can be used to monitor the effectiveness of therapy. **Galactitol is a product of an alternate pathway for galactose metabolism and can be measured in the urine. Correlation with other measures may not be perfect. **Total body oxidation of 13C-galactose to 13CO 2 in breath is a good predictor of outcome and differentiates forms of galactosemia that reduce GALT activity in erythrocytes, but not liver Variant Galactosemia *partial impairment of GALT activity (2% to 10% residual activity) *some aspects of classical galactosemia, such as early cataracts, mild mental retardation with ataxia, and growth retardatio *may have dyspraxic speech, and females may have amenorrhea or early menopause Common Long Term Problems *memory problems *neurological problems (tremors and trouble with balance and gait). *Cataracts Prevalence *Classic galactosemia -- based on the results of newborn screening programs, is approximately 1/30,000 *Carrier rate is 1:112 Genotype-Phenotype Correlations *Significant correlations being found *arginine substitution for a glutamine at amino acid position 188 (Q188R) accounts for about 70% of the G alleles in the Caucasian population with northern European ethnicity. Homozygotes have no enzyme activity *some studies found greater proportion of patients with a poor outcome were homozygous for the Q188R mutation, and a greater proportion with a good outcome were not homozygous for the Q188R *Duarte variant is the allele in which an aspartate substituted for asparagine at position 314 (N314D) imparts bioinstability to the GALT enzyme. *In the homozygous state (D/D or N314D/N314D), erythrocyte GALT enzyme activity is reduced by only 50%. *Compound heterozygotes with this mutation (i.e., D/G or N314D/Q188R) have good prognoses and it is not clear whether dietary intervention is required *The S135L allele, in which a leucine is substituted for serine at amino acid 135, is prevalent in Africa. African-Americans with galactosemia and this allele in either homozygous or compound heterozygous state have a good prognosis because of lack of neonatal hepatotoxicity and chronic problems if therapy is begun early *An asparagine substitution for a lysine at position 285 (K285N) is prevalent in southern Germany, Austria, and Croatia and has a poor prognosis for neurological and cognitive dysfunction in either the homozygous state or compound heterozygous state with Q188R. Differential Diagnosis *for neonatal hepatotoxicity **infectious diseases **obstructive biliary disease **other metabolic diseases such as (Niemann-Pick Disease, Type C1 and Wilson disease). *Galactokinase deficiency **should be considered in patients who have cataracts and galactosemia but healthy **have normal GALT activity **reduced galactokinase activity is diagnostic and is what causes cataracts *Epimerase deficiency **should be considered in patients who have liver disease, sensorineural deafness, failure to thrive, and elevated galactose-1-phosphate, but normal GALT activity **Detection of reduced epimerase activity is diagnostic Management *Immediate dietary intervention is indicated in infants whose GALT activity is less than 10% of control activity *Human milk, cow's milk and many formulas have lactose so all of these milk products must be replaced by a formula such as Isomil or Prosobee *Ideally blood gal-1-p level below 3 to 4 mg/100 ml *galactose-restricted diet should keep blood gal-1-p at this level, while containing enough nutrients for normal body function *The diet allows most protein-containing foods other than milk and milk products. Fruits, vegetables, grains, breads, fats and sugars are acceptable, as long as they do not have ingredients that contain galactose *Food labels should be read carefully *Medicines should be checked because lactose often an inactive ingredient *Dietary supplements only taken when recommended because inactive ingredients not listed *people with galactosemia should have a regular daily supplement of calcium either from a soy formula or tablets *Dietary restrictions on all lactose-containing continue throughout life *Uridine supplements have not been of value. *Recent research suggests that despite exogenous galactose restriction, endogenous galactose production may approach 2.0 g per day *The efficiency of restricting lactose in the diets of women who are at risk for having a child with galactosemia is unknown. *Agreement has not been reached on whether individuals with variant forms of galactosemia with residual GALT activity in the range of 3% to 20% should be restricted from galactose intake during infancy and early childhood --possible that dietary restriction of galactose might prevent sequelae such as cataracts, ataxia, dyspraxic speech, and cognitive deficits. Risk To Family Members *Unaffected parents of an affected individual are obligate heterozygotes and carry at one disease-causing GALT allele *Such carriers are asymptomatic and do not develop galactosemia *Appropriate and can be important to determine the disease-causing GALT alleles in the parents of an affected child to establish the risk for galactosemia in future pregnancies *Affected individuals have a risk for premature ovarian failure, but may have children. Children born to one parent with (G/G) galactosemia and one parent with two normal alleles (N/N) are obligate heterozygotes (N/G) *If one parent is affected (G/G) and the other parent is a carrier for a G allele (N/G or D/G), the child has a 50% chance of being a heterozygote and a 50% chance of having G/G galactosemia Prenatal Testing *possible for fetuses at 25% risk for classical (G/G) galactosemia using either GALT enzyme activity or molecular genetic testing if the disease-causing GALT mutations in the family are known *Enzyme analysis and molecular diagnosis rely upon cells obtained by chorionic villus sampling (CVS) at about 10-12 weeks' gestation* or amniocentesis at 16-18 weeks' gestation. Resources *Galactosemia Support Group :31 Cotysmore :Sutton Coldfield :West Midlands, B75 6BJ, UK :Phone: 0121 378 5143 *Adult Metabolic Transition Project :depts.washington.edu/transmet/gal.html *Children Living with Inherited Metabolic Diseases (CLIMB) :The Quadrangle, Crewe Hall :Weston Road, Crewe :Cheshire, CW1 6UR, UK :Phone: 01270 250221 :Fax: 01270 250224 :www.climb.org.uk *http://www.tdh.state.tx.us/newborn/handbook.htm -- great website for parent of newly diagnosed child *http://www.galactosemia.org/ -- website for parent support group Notes The information in this outline was last updated in 2001. This material has been imported fom the wikibook "Genetic counseling"[ http://en.wikibooks.org/wiki/Genetic_counseling] under the GNU Free Documentation License.